# Gut Microbiota and Host Regulatory Cross-Talk in Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $467,841

## Abstract

Project Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disorder with no known cure and poorly
understood pathogenesis. IPF results in significant reductions in quality of life, recurrent hospitalizations and is
fatal. We and others have shown that pulmonary immunity is dysregulated in IPF. The bacteria and host
environment of the human gut - the gut microbiome - has a profound impact on human immunity. The gut
microbiome is a key regulator of pulmonary immunity, a consistent biological observation across several
experimental models. In a key finding, recently published, we have shown that germ free (GF) mice –
experimental mice devoid of a microbiome – are protected from pulmonary fibrosis related mortality. In human
patients with IPF, the bacterial burden of the lung predicts mortality and the lungs bacterial diversity correlates
with pulmonary inflammation. While the microbiome predicts outcomes, key regulatory interactions between
the host, lung and gut microbiota remain unknown.
The central hypothesis of this proposal is that key gut microbiota, namely Bifidobacterium spp, act as master
regulators of pulmonary immunity in lung fibrosis, shaping host defense, associated inflammation and
modifying parenchymal repair after lung injury. The rationale for this proposal is that this work will augment our
current knowledge of IPF pathogenesis and further the foundational basis for microbiome based therapies in
chronic lung disease. We will accomplish this through the following experimental aims:
Specific Aim 1: To determine key Bifidobacteria by-products and metabolites that contribute to outcomes in
pre-clinical models of pulmonary fibrosis using pre-biotic diet modifications, germ free (GF) and gnotobiotic
mice, 16S rRNA gene sequencing, functional metagenomics and metabolomics.
Specific Aim 2: To determine the host related cellular and molecular mechanisms through which
Bifidobacterium spp modify outcomes in pulmonary fibrosis using pre-clinical models of pulmonary fibrosis in
conventional and GF derived T cell, IL-10 and IL-17 transgenic models, T cell adoptive transfer and multicolor
flow cytometry mediated characterization of lung cellular immunity.
Specific Aim 3: To determine the immunogenic and fibrogenic effects of gut microbiota from patients with IPF.
Gut microbiota from patients with IPF will be identified and correlated with disease severity and clinical
outcomes. Regulatory T cell phenotype from patients with IPF will be correlated with gut diversity and taxa.
This translational approach will use advanced mechanistic tools to 1) improve our understanding of complex
immune-microbiota interactions that occur in pre-clinical models of lung fibrosis, 2) identify modifiable host and
microbiota related targets in lung fibrosis and finally 3) advance the foundation for microbiome based therapies
in chronic lung disease.

## Key facts

- **NIH application ID:** 10885076
- **Project number:** 5R01HL162659-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Noel O'Dwyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,841
- **Award type:** 5
- **Project period:** 2022-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885076

## Citation

> US National Institutes of Health, RePORTER application 10885076, Gut Microbiota and Host Regulatory Cross-Talk in Pulmonary Fibrosis (5R01HL162659-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10885076. Licensed CC0.

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